Reprogramming the system(Prof Ashford)

Question 1

List the four treatments of preventing/treating obesity

Answer 1

Lifestyle change, CBT, bariatric surgery (reserved for morbid obesity) and therapeutic agents to reduce body weight

Question 2

Give examples of noradrenergics in weight loss and give a brief description

Answer 2

Diethylpropion, mazindol and phentermine. Appetite suppressants that inhibit the noradrenaline uptake. They have serious CV side effects.

Question 3

Give examples of serotonergics in weight loss and give a brief description

Answer 3

Fenfluramine, dexfenfluramine and fluoxetine. Is an appetite suppressant that acts on the 5-HT system

Question 4

What is fen-phen and what are its side effects

Answer 4

A combination of fenfluramine and phentermine that can cause potentially fatal pulmonary hypertension and heart valve problems

Question 5

Give examples of sibutramine in weight loss and give a brief description

Answer 5

Meridia and reductil. They decrease food intake and may also increase thermogenesis by selectively inhibiting the re-uptake of noradrenaline, 5-HT and dopamine. They have a CV and stroke risk

Question 6

Give the other name of rimonabant in weight loss and give a brief description

Answer 6

It counteracts obesity by antagonising the CB1 receptor. Also have potential with addiction (smoking, alcohol, cocaine and opiates. and can improve short term memory. Can cause severe depression and anxiety in some patients as a side effect. Also as endocannabinoids are neuroprotective there are worries about neurodegeneration

Question 7

Give a brief description of orlistat

Answer 7

It inhibits pancreatic lipase by decreasing triglyceride absorption. It also reduces efficiency of fat absorption in the small intestine but has side effects such as cramping, bloating, flatulence, abdo pain and diarrhoea. You also need to take vitamine supplements due to loss of fat-soluable vitamine and it is not particularly effective.

Question 8

List some new drugs being developed

Answer 8

Lorcaserin, qsymia, contrave and liraglutide

Question 9

Give a description of lorcaserin

Answer 9

Agonist at the 5-HT2c receptor but can cause heart valve problems

Question 10

Give a description of qsymia

Answer 10

Its a combination therapy of phentermine and topiramate (an anti-convulsant) which has cardiac and psychiatric side-effects

Question 11

Give a description of contrave

Answer 11

Is also known as mysimba. Is a combination therapy of bupropion (a dopamine re-uptake inhibitor) and naltrexone (opioid antagoist). This works because bupropion activates POMC neurons and naltrexone suppresses POMC inhibition

Question 12

Give a description of liraglutide

Answer 12

It is a GLP-1 agonist licenced for T2DM that has to be administered I.V. It also has a potential for thyroid and pancreatic cancer

Question 13

What meds should and should not be used in patients with obesity, uncontrolled hypertension and/or heart disease

Answer 13

Do not use sympathomometics (phentermine or diethypropion)

The preferred agents are lorcaserin or orlistat

Question 14

What meds should be used in patients with T2DM and obesity

Answer 14

GLP-1 analogues, SGLT-2 inhibitors, metformin and pramlintide (induce weight loss)

Question 15

What anti-diabetic meds cause weight gain

Answer 15

Insulin, insulin secretagogues and TZDs

Question 16

Give a description of SGLT-2 inhibitors

Answer 16

Inhibit renal glucose transport and increase urinary glucose excretion. They have beneficial effects on body weight, BP and lipid

Question 17

Describe the molecule DDP4

Answer 17

Is a serine protease that cleaves a number of substrates such as GLP-1 and GIP

Question 18

How do DDP4 inhibitors work

Answer 18

Inhibition of DPP4 elevates GLP-1/GIP and this stimulates insulin secretion

Question 19

What is the definition of hybrid drugs

Answer 19

Single molecules acting on more than one receptor

Question 20

What are the three types of bariatric surgery

Answer 20

Adjustable gastric band (AGB), roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy

Question 21

Describe AGB surgery

Answer 21

Band at the top of the stomach to limit food entry

Question 22

Describe RYGB surgery

Answer 22

The digestive tract-re-route, by-passing most of the stomach and part of small intestine. This acts to G.I. transit of food.

Question 23

Describe VSG surgery

Answer 23

Reduces stomach size by chopping some off and this lowers food intake and gastric emptying is increased

Question 24

Does bariatric surgery work?

Answer 24

Yes it does in multiple ways. Produces a substantial weight loss of 50% in one year that is is sustainable and can induce a high level of complete resolution on T2DM. This improvement in glucose homeostasis and insulin sensitivity can occur within a week

Question 25

What is celastrol?

Answer 25

A leptin sensitiser that can cause weight gain (in DIO mice) due to lowered food intake and later increased energy expenditure

Question 26

What is an alternative to targeting calorie restriction?

Answer 26

Targeting energy expenditure (cellular bioenergetics)

Question 27

What are the three types of energy expenditure in humans

Answer 27

1) Obligatory energy expenditure (basic cell and organ physiological needs) 2) Physical activity (variable-advances in tech/transport) 3) Adaptive thermogenesis

Question 28

Describe adaptive thermogenesis

Answer 28

Heat production by an organism in response to changes in environmental temperature or diet. This occurs in BAT and skeletal muscle

Question 29

Describe the two types of cold induced thermogenesis

Answer 29

Shivering (skeletal muscle) or non-shivering (brown fat)

Question 30

Does feeding increase or decrease energy expenditure

Answer 30

Feeding increases use of energy (have energy to burn)

Question 31

What type of energy is often lost when ATP is produced and what causes this?

Answer 31

Heat due to proton leakage

Question 32

How does the body utilize heat produced by proton leakage

Answer 32

There can be a regulated proton leak in the BAT by UCP-1 (an inner mitochondrial transmembrane protein). UCP-1 allows protons to re-enter the mitochondrial matrix from intermembrane space with heat produced instead of ATP

Question 33

What activates UCP-1

Answer 33

Long chain fatty acids and free radicals

Question 34

What are 'brite' adipocytes

Answer 34

Basically brown adipose cells surrounded by white adipose cells

Question 35

What can trigger a precursor to become brite adipocytes

Answer 35

Cold temperatures and chronic beta-3 agonism

Question 36

Which part of the nervous system switches on cold and diet induced thermogenesis

Answer 36

The sympathetic nervous system

Question 37

What is different about brown/brite adipocytes

Answer 37

They have numerous oxidative and naturally uncoupled mitochondria that act to dissipate chemical energy (glucose and fatty acids) as heat

Question 38

What can bone morphogenetic proteins (BMPs) do to BAT

Answer 38

Promote BAT differentiation

Question 39

What does FGF21 do

Answer 39

Induces expression of thermogenic genes in BAT and WAT

Question 40

What is the stem cell biology approach to BAT

Answer 40

Isolate progenitor cells (with liposuction) and stimulate them with known factors to promote BAT differentiation or transect with genes known to induce browning and then transplant back into donor

Question 41

What is the uncoupling targeted therapeutic agent called, how does it work and what is its side effect

Answer 41

2,4-Dintrophenol is a non-selective coupler of mitochondrial oxidation (proton ionophore) which collapses mitochondrial proton gradient with no ATP produced and lots of heat. This can cause fatal hyperthermia.

Question 42

Where are the UCP 1-5 located in the body

Answer 42

UCP1 in adipose tissue UCP2,4 and 5 in neurons UCP2 and 3 in muscle

Question 43

What is SkQ1

Answer 43

A group of antioxidants (reactive oxidative species (ROS) scavenger)) that targets the mitochondria anti-ageing neuroprotective

Question 44

What is C12TPP

Answer 44

It acts to uncouple mitochondria by acting to recycle endogenous fatty acids

Question 45

How does exercise effect the brain

Answer 45

Improves neuronal health and resilience by promoting synaptic plasticity and increasing neurogenesis and angiogenesis. It also increases firing of POMC neurons and diminishes firing of AgRP neurons